07 July 2010

The question is obviously important, at least as long as there are disputes about whether introns have "functions" and whether science ignored them for decades.

Now, I can't help the ID people with their propensity for repeating falsehoods about the history of "junk DNA" and the role of "Darwinism" in its characterization. But I do think we can move a little closer together on this intron thing. So, first a discussion of the types of functions that are associated with introns then some comments on my specific dispute with Richard Sternberg.

1. Introns facilitate alternative splicing.

Richard Sternberg's piece at that obnoxious propaganda mill does have a nice description of the process of alternative splicing. He describes it as follows:

What is alternative splicing? Imagine that the initial RNA derived from its DNA template has the organization A—B—C—D—E—F, where the letters represent blocks that specify amino acid sequences and the dashes in between the letters stand for introns. Alternative splicing enables multiple proteins to be constructed given the same RNA precursor, say, ABCDF, ACDEF, BCDEF, and so forth. In this way, hundreds or thousands of proteins can be derived from a single gene.

Yes, that's alternative splicing. Because the coding sequence is divided into chunks (those are the "blocks that specify amino acid sequences" and they're called exons), it can be stitched together in different ways. It's not clear how much of this capacity is actually used by cells, but the capacity is there, and the existence of introns is one reason why.

So is that a "function" of introns? Well, sure, but Richard Sternberg was wrong to think that pointing to alternative splicing would suffice as a refutation of the argument that I and others make when ID apologists argue that introns are "functional." First off, he should have known that I am well aware of alternative splicing. I've discussed the issue with Mike Gene, who proposes that introns facilitated the evolution of multicellular life. But more importantly, he's ignoring the real challenge: the existence of alternative splicing doesn't explain the size of introns, and the vastness of "intron space" in the human genome isn't accounted for, even to the most trivial extent, by splicing and splice codes. As I explained in the last post, introns vary enormously in size, and the average human intron is hundreds of times bigger than it needs to be in order to provide splice junctions and the signals that trigger alternative splicing.

And we have good reason to think that intron size is completely irrelevant to the function of alternative splicing. This is a point that Mike Gene has figured out, to his credit: the splice junctions, created in part by the presence of introns, are the elements that are conserved in related species. The introns themselves are typically poorly conserved. (Think about the jarring size difference between the human and chicken versions of the Factor VIII gene; the introns are far smaller in the chicken gene, but both genes have exactly the same number of them, meaning that both genes have the same number of splice junctions.)

Yes, introns facilitate alternative splicing. We all knew that. What we don't know is what the remaining 99+% of intronic sequence is doing, and why it seems to be largely dispensable for normal biological function.

2. Introns harbor functional non-coding DNA elements.

Genomes contain lots of interesting components – usually tiny compared to genes and other elements – that are involved in the control of gene expression. These are stretches of sequence that may be markers, or codes, that say "make more of this" or "make less of that" in a code that will only be read under certain circumstances (like, say, in a nerve cell). Or they may be made into microRNAs, which can control the levels of production of particular proteins. (Some of the "genes" that encode microRNAs have been known for many years, but only in the last decade have their mode of operation and their full number been worked out.) Or they may be made into other kinds of RNA that can influence gene expression in various other ways.

And all of those things have been found in introns. In a small number of cases, these intronic elements have been shown to exert significant influences on gene expression, development, or metabolism. A recent issue of Science included two reports on one such example, and that's a sign of how rarely such functional connections are made – commonplace observations are not featured in Science.

How much more of intron space is accounted for by these functional elements? No one knows, but let's try this for a quick estimate. Let's say that each human intron contains three such elements, for a total of 600,000 of them. And let's say that the functional elements average 100 base pairs in length. Both of those estimates seem quite high to me, based on the current literature; again, the number of elements known to influence development or function is very low. But let's go with our estimate: it leads to a total of 6o million base pairs in intron space that would be postulated to have function. How big is intron space? In humans, it's around 768 million base pairs.

3. Introns may regulate the speed of the process of gene expression.

Are there other ways in which introns may exert "function"? One idea is that the insertion of these huge intervening regions can slow down the transcription process, resulting in a means by which introns can influence gene expression just by being there. Sort of like a speed bump. And perhaps related, genes that are used a lot (because they're expressed at high levels in all sorts of cells) tend to have really small introns. We'll come back to that observation in the next post.

Well then, what is it that Richard Sternberg and I disagree about? It's hard to tell. He interpreted my criticism of Steve Meyer incorrectly, and assumed that I am unaware of alternative splicing and of the existence of various types of regulatory elements that appear in introns. I hope he agrees that the anti-"Darwinian" narrative told by many of his Discovery Institute colleagues is nonsense, and if not then we do have a serious problem. But maybe he's inclined to think that a dominant fraction of the vast bulk of intron space is devoted to specific functions. That wouldn't make him stupid, and in fact it would put him in the company of the true Darwinists, an irony that none of his propagandizing fellow travelers seems willing to acknowledge. (Corrections on this count are most welcome.) What it does mean is that he has a lot of work to do. The human genome contains an enormous amount of intron space, and it's not even a particularly large genome as they come.

So, Richard Sternberg, we can agree to disagree about the potential functional relevance of intron space and of the one-third of the human genome composed of transposable elements and their debris. But there's really no room for a claim that the human genome is a tightly-organized system for information storage and retrieval, based on a few reports of "function" for some non-coding DNA elements. There are good reasons to doubt that conclusion, just based on what we know about introns. We'll deal with that in the next post.

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Introns. Let's think about this, people. Part III.

What does it mean to claim that an intron has a function?

The question is obviously important, at least as long as there are disputes about whether introns have "functions" and whether science ignored them for decades.

Now, I can't help the ID people with their propensity for repeating falsehoods about the history of "junk DNA" and the role of "Darwinism" in its characterization. But I do think we can move a little closer together on this intron thing. So, first a discussion of the types of functions that are associated with introns then some comments on my specific dispute with Richard Sternberg.

1. Introns facilitate alternative splicing.

Richard Sternberg's piece at that obnoxious propaganda mill does have a nice description of the process of alternative splicing. He describes it as follows:

What is alternative splicing? Imagine that the initial RNA derived from its DNA template has the organization A—B—C—D—E—F, where the letters represent blocks that specify amino acid sequences and the dashes in between the letters stand for introns. Alternative splicing enables multiple proteins to be constructed given the same RNA precursor, say, ABCDF, ACDEF, BCDEF, and so forth. In this way, hundreds or thousands of proteins can be derived from a single gene.

Yes, that's alternative splicing. Because the coding sequence is divided into chunks (those are the "blocks that specify amino acid sequences" and they're called exons), it can be stitched together in different ways. It's not clear how much of this capacity is actually used by cells, but the capacity is there, and the existence of introns is one reason why.

So is that a "function" of introns? Well, sure, but Richard Sternberg was wrong to think that pointing to alternative splicing would suffice as a refutation of the argument that I and others make when ID apologists argue that introns are "functional." First off, he should have known that I am well aware of alternative splicing. I've discussed the issue with Mike Gene, who proposes that introns facilitated the evolution of multicellular life. But more importantly, he's ignoring the real challenge: the existence of alternative splicing doesn't explain the size of introns, and the vastness of "intron space" in the human genome isn't accounted for, even to the most trivial extent, by splicing and splice codes. As I explained in the last post, introns vary enormously in size, and the average human intron is hundreds of times bigger than it needs to be in order to provide splice junctions and the signals that trigger alternative splicing.

And we have good reason to think that intron size is completely irrelevant to the function of alternative splicing. This is a point that Mike Gene has figured out, to his credit: the splice junctions, created in part by the presence of introns, are the elements that are conserved in related species. The introns themselves are typically poorly conserved. (Think about the jarring size difference between the human and chicken versions of the Factor VIII gene; the introns are far smaller in the chicken gene, but both genes have exactly the same number of them, meaning that both genes have the same number of splice junctions.)

Yes, introns facilitate alternative splicing. We all knew that. What we don't know is what the remaining 99+% of intronic sequence is doing, and why it seems to be largely dispensable for normal biological function.

2. Introns harbor functional non-coding DNA elements.

Genomes contain lots of interesting components – usually tiny compared to genes and other elements – that are involved in the control of gene expression. These are stretches of sequence that may be markers, or codes, that say "make more of this" or "make less of that" in a code that will only be read under certain circumstances (like, say, in a nerve cell). Or they may be made into microRNAs, which can control the levels of production of particular proteins. (Some of the "genes" that encode microRNAs have been known for many years, but only in the last decade have their mode of operation and their full number been worked out.) Or they may be made into other kinds of RNA that can influence gene expression in various other ways.

And all of those things have been found in introns. In a small number of cases, these intronic elements have been shown to exert significant influences on gene expression, development, or metabolism. A recent issue of Science included two reports on one such example, and that's a sign of how rarely such functional connections are made – commonplace observations are not featured in Science.

How much more of intron space is accounted for by these functional elements? No one knows, but let's try this for a quick estimate. Let's say that each human intron contains three such elements, for a total of 600,000 of them. And let's say that the functional elements average 100 base pairs in length. Both of those estimates seem quite high to me, based on the current literature; again, the number of elements known to influence development or function is very low. But let's go with our estimate: it leads to a total of 6o million base pairs in intron space that would be postulated to have function. How big is intron space? In humans, it's around 768 million base pairs.

3. Introns may regulate the speed of the process of gene expression.

Are there other ways in which introns may exert "function"? One idea is that the insertion of these huge intervening regions can slow down the transcription process, resulting in a means by which introns can influence gene expression just by being there. Sort of like a speed bump. And perhaps related, genes that are used a lot (because they're expressed at high levels in all sorts of cells) tend to have really small introns. We'll come back to that observation in the next post.

Well then, what is it that Richard Sternberg and I disagree about? It's hard to tell. He interpreted my criticism of Steve Meyer incorrectly, and assumed that I am unaware of alternative splicing and of the existence of various types of regulatory elements that appear in introns. I hope he agrees that the anti-"Darwinian" narrative told by many of his Discovery Institute colleagues is nonsense, and if not then we do have a serious problem. But maybe he's inclined to think that a dominant fraction of the vast bulk of intron space is devoted to specific functions. That wouldn't make him stupid, and in fact it would put him in the company of the true Darwinists, an irony that none of his propagandizing fellow travelers seems willing to acknowledge. (Corrections on this count are most welcome.) What it does mean is that he has a lot of work to do. The human genome contains an enormous amount of intron space, and it's not even a particularly large genome as they come.

So, Richard Sternberg, we can agree to disagree about the potential functional relevance of intron space and of the one-third of the human genome composed of transposable elements and their debris. But there's really no room for a claim that the human genome is a tightly-organized system for information storage and retrieval, based on a few reports of "function" for some non-coding DNA elements. There are good reasons to doubt that conclusion, just based on what we know about introns. We'll deal with that in the next post.